Parvalbumin subtypes of cerebellar Purkinje cells contribute to differential intrinsic firing properties.

Purkinje cells (PCs) are central to cerebellar information coding and appreciation for the diversity of their firing patterns and molecular profiles is growing. Heterogeneous subpopulations of PCs have been identified that display differences in intrinsic firing properties without clear mechanistic insight into what underlies the divergence in firing parameters. Although long used as a general PC marker, we report that the calcium binding protein parvalbumin labels a subpopulation of PCs, based on high and low expression, with a conserved distribution pattern across the animals examined. We trained a convolutional neural network to recognize the parvalbumin subtypes and create maps of whole cerebellar distribution and find that PCs within these areas have differences in spontaneous firing that can be modified by altering calcium buffer content. These subtypes also show differential responses to potassium and calcium channel blockade, suggesting a mechanistic role for variability in PC intrinsic firing through differences in ion channel composition. It is proposed that ion channels drive the diversity in PC intrinsic firing phenotype and parvalbumin calcium buffering provides capacity for the highest firing rates observed. These findings open new avenues for detailed classification of PC subtypes.

Differential serotonin transporter (5-HTT) and 5-HT2 receptor density in limbic and neocortical areas of adults and children with autism spectrum disorders: implications for selective serotonin reuptake inhibitor efficacy.

As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14-19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5-HT transporter (5-HTT) as well as to 5-HT2 and 1A receptors (5-HT2, 5-HT1A ) was quantified in superficial and deep layers of each region using the ligands [3 H]-citalopram (5-HTT), [3 H]-ketanserin (5-HT2 ), and [3 H]-8-OH-DPAT (5-HT1A ). A Welch's t-test was utilized to compare receptor densities (Bmax ), revealing a statistically significant decrease in 5-HTT within the ACC of the entire autism cohort. There was also a decrease in 5-HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of Bmax values plotted against age, shows a significantly lower intercept for 5-HTT in autism (p = 0.025). 5-HT2 density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5-HTT within the ACC in individuals with autism, while decreases in 5-HT2 density are age-dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (KD ) across all regions and ligands examined.

India ink to 3D imaging: The legacy of Dr. Deepak "Dee" N. Pandya and his influence on generations of neuroanatomists.

Dr. Deepak "Dee" Pandya spent his career as an internal medicine physician as well as in his respective laboratories at the Bedford, Massachusetts Veterans Administration Hospital and at Boston University School of Medicine. His achievements mapping out the cytoarchitecture and connectivity of areas all over the nonhuman primate brain and small mammals are unparalleled. Dee made numerous discoveries and created painstakingly detailed reports, which impacted the field of neuroanatomy and expanded our perceptions of the many diverse inputs and suggestive functions of specific brain regions. The "old school" methods employed from microscopic work to detailed analyses yielded a product that was accurate and exciting all at the same time. We will all miss Dee's smile and tender manner, but more so, we will miss his wonderful and patient mentorship during the precious time we all spent with him. His mentorship resulted in all of his trainees becoming better scientists and left us with the understanding that people like Dee only come by once in a lifetime. In this tribute article for this special issue in the Journal of Comparative Neurology (JCN), the authors describe some of the tedious methods that were used to present our work as a way to provide insight into the extraordinary time and effort it took to produce and publish our articles with Dee in JCN. Dee's work with his colleagues set the stage for more modern methods of counting and mapping neuronal populations presented here, paving the way for such technologies as artificial intelligence and light sheet imaging to advance the field forward to reach new and exciting discoveries.

Consensus paper: pathological role of the cerebellum in autism.

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Region-Specific Alterations of Perineuronal Net Expression in Postmortem Autism Brain Tissue.

Genetic variance in autism spectrum disorder (ASD) is often associated with mechanisms that broadly fall into the category of neuroplasticity. Parvalbumin positive neurons and their surrounding perineuronal nets (PNNs) are important factors in critical period plasticity and have both been implicated in ASD. PNNs are found in high density within output structures of the cerebellum and basal ganglia, two regions that are densely connected to many other brain areas and have the potential to participate in the diverse array of symptoms present in an ASD diagnosis. The dentate nucleus (DN) and globus pallidus (GP) were therefore assessed for differences in PNN expression in human postmortem ASD brain tissue. While Purkinje cell loss is a consistent neuropathological finding in ASD, in this cohort, the Purkinje cell targets within the DN did not show differences in number of cells with or without a PNN. However, the density of parvalbumin positive neurons with a PNN were significantly reduced in the GP internus and externus of ASD cases, which was not dependent on seizure status. It is unclear whether these alterations manifest during development or are a consequence of activity-dependent mechanisms that lead to altered network dynamics later in life.

Transcriptomic analysis of isolated and pooled human postmortem cerebellar Purkinje cells in autism spectrum disorders.

At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors. Laser capture microdissection was performed to obtain pure PC populations from a cohort of postmortem control and ASD cases and transcriptional profiles were compared. The 427 differentially expressed genes were enriched for gene ontology biological processes related to developmental organization/connectivity, extracellular matrix organization, calcium ion response, immune function and PC signaling alterations. Given the complexity of PCs and their far-ranging roles in response to sensory stimuli and motor function regulation, understanding transcriptional differences in this subset of cerebellar cells in ASD may inform on convergent pathways that impact neuronal function.

Prenatal protein malnutrition alters the proportion but not numbers of parvalbumin-immunoreactive interneurons in the hippocampus of the adult Sprague-Dawley rat.

Prenatal protein malnutrition alters the structure and function of the adult rat hippocampal formation. The current study examines the effect of prenatal protein malnutrition on numbers of parvalbumin-immunoreactive (PV-IR) GABAergic interneurons, which are important for perisomatic inhibition of hippocampal pyramidal neurons. Brain sections from prenatally protein malnourished and normally nourished rats were stained for parvalbumin and PV-IR neurons were quantified using stereology in the dentate gyrus, CA3/2 and CA1 subfields, and the subiculum for both cerebral hemispheres. Results demonstrated that prenatal malnutrition did not affect the number of PV-IR interneurons in the hippocampus. Since prenatal protein malnutrition reduces total neuron numbers in the CA1 subfield (1), this results in an altered ratio of PV-IR interneurons to total neuronal numbers (from 1:22.9 in controls to 1:20.5 in malnourished rats). Additionally, there was no hemispheric asymmetry of either PV-IR neuron numbers or ratio of PV-IR:total neuron numbers.

Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism.

Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.

Regulation of Neural Circuit Development by Cadherin-11 Provides Implications for Autism.

Autism spectrum disorder (ASD) is a neurologic condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical Type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels, but downregulated CDH11. We used Cdh11 knock-out (KO) mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism. Cdh11-/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated in Cdh11 KO brains. Additionally, excitatory synaptic markers neuroligin-1 and postsynaptic density (PSD)-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.

Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism.

Autism is a behaviorally defined neurodevelopmental disorder and among its symptoms are disturbances in face and emotional processing. Emerging evidence demonstrates abnormalities in the GABAergic (gamma-aminobutyric acid) system in autism, which likely contributes to these deficits. GABA(B) receptors play an important role in modulating synapses and maintaining the balance of excitation-inhibition in the brain. The density of GABA(B) receptors in subjects with autism and matched controls was quantified in the anterior and posterior cingulate cortex, important for socio-emotional and cognitive processing, and the fusiform gyrus, important for identification of faces and facial expressions. Significant reductions in GABA(B) receptor density were demonstrated in all three regions examined suggesting that alterations in this key inhibitory receptor subtype may contribute to the functional deficits in individuals with autism. Interestingly, the presence of seizure in a subset of autism cases did not have a significant effect on the density of GABA(B) receptors in any of the three regions.

Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry.

Autism spectrum disorder (ASD) is behaviorally defined and diagnosed by delayed and/or impeded language, stereotyped repetitive behaviors, and difficulties with social interactions. Additionally, there are disruptions in motor processing, which includes the intent to execute movements, interrupted/inhibited action chain sequences, impaired execution of speech, and repetitive motor behaviors. Cortical loops through basal ganglia (BG) structures are known to play critical roles in the typical functioning of these actions. Specifically, corticostriate projections to the dorsal striatum (caudate and putamen) convey abundant input from motor, cognitive and limbic cortices and subsequently project to other BG structures. Excitatory dopamine (DA) type 1 receptors are predominantly expressed on GABAergic medium spiny neurons (MSNs) in the dorsal striatum as part of the "direct pathway" to GPi and SNpr whereas inhibitory DA type 2 receptors are predominantly expressed on MSNs that primarily project to GPe. This study aimed to better understand how this circuitry may be altered in ASD, especially concerning the neurochemical modulation of GABAergic MSNs within the two major BG pathways. We utilized two classical methods to analyze the postmortem BG in ASD in comparison to neurotypical cases: ligand binding autoradiography to quantify densities of GABA-A, GABA-B, 5-HT2, and DA type 1 and 2 receptors and in situ hybridization histochemistry (ISHH) to quantify mRNA for D1, D2 receptors and three key GABAergic subunits (α1, ß2, and γ2), as well as the GABA synthesizing enzymes (GAD65/67). Results demonstrated significant increases in D2 mRNA within MSNs in both the caudate and putamen, which was further verified by proenkephalin mRNA that is co-expressed with the D2 receptor in the indirect pathway MSNs. In contrast, all other GABAergic, serotonergic and dopaminergic markers in the dorsal striatum had comparable labeling densities. These results indicate alterations in the indirect pathway of the BG, with possible implications for the execution of competing motor programs and E/I imbalance in the direct/indirect motor feedback pathways through thalamic and motor cortical areas. Results also provide insights regarding the efficacy of FDA-approved drugs used to treat individuals with ASD acting on specific DA and 5-HT receptor subtypes.

Development of a 3-D Organoid System Using Human Induced Pluripotent Stem Cells to Model Idiopathic Autism.

Autism spectrum condition (ASC) is a complex set of behavioral and neurological responses reflecting a likely interaction between autism susceptibility genes and the environment. Autism represents a spectrum in which heterogeneous genetic backgrounds are expressed with similar heterogeneity in the affected domains of communication, social interaction, and behavior. The impact of gene-environment interactions may also account for differences in underlying neurology and wide variation in observed behaviors. For these reasons, it has been difficult for geneticists and neuroscientists to build adequate systems to model the complex neurobiology causes of autism. In addition, the development of therapeutics for individuals with autism has been painstakingly slow, with most treatment options reduced to repurposed medications developed for other neurological diseases. Adequately developing therapeutics that are sensitive to the genetic and neurobiological diversity of individuals with autism necessitates personalized models of ASC that can capture some common pathways that reflect the neurophysiological and genetic backgrounds of varying individuals. Testing cohorts of individuals with and without autism for these potentially convergent pathways on a scalable platform for therapeutic development requires large numbers of samples from a diverse population. To date, human induced pluripotent stem cells (iPSCs) represent one of the best systems for conducting these types of assays in a clinically relevant and scalable way. The discovery of the four Yamanaka transcription factors (OCT3/4, SOX2, c-Myc, and KLF4) [1] allows for the induction of iPSCs from fibroblasts [2], peripheral blood mononuclear cells (PBMCs, i.e. lymphocytes and monocytes) [3, 4], or dental pulp cells [5] that retain the original genetics of the individual from which they were derived [6], making iPSCs a powerful tool to model neurophysiological conditions. iPSCs are a readily renewable cell type that can be developed on a small scale for boutique-style proof-of-principle phenotypic studies and scaled to an industrial level for drug screening and other high-content assays. This flexibility, along with the ability to represent the true genetic diversity of autism, underscores the importance of using iPSCs to model neurophysiological aspects of ASC.

Density of cerebellar basket and stellate cells in autism: evidence for a late developmental loss of Purkinje cells.

Alterations in the cerebellum have been described as a neuropathological feature of autism. Although numerous studies have focused on the Purkinje cell (PC), the projection neuron of the cerebellar cortex, PC function is critically dependent on their innervation by the GABAergic basket cells (BCs) and stellate cells (SCs) in the cerebellar molecular layer. The present study was designed to determine whether there are differences in the packing density of these inhibitory interneurons or whether the ratio of these interneurons to PCs differs in autistic and age-matched control brains. The GABAergic interneurons were identified by using immunohistochemistry for parvalbumin (PV) in serial sections from the posterior cerebellar lobe of six autistic and four control brains and counted using stereological principles. Prior PC counts in the same area on adjacent sections (Whitney et al., 2008) were available and were used to calculate the number of BCs and SCs per PC. In this sample of brains, no statistically significant difference was detected between the autistic and the control groups in the density of BCs or SCs (P = 0.44 and P = 0.84, respectively) or in the number of BCs or SCs per PC (P = 0.47 and P = 0.44, respectively). The preservation of BCs and SCs, in the presence of the reduced PC numbers as found in at least two, and possibly three, of these six autistic cases (Whitney et al., 2008) suggests that PCs were generated, migrated to their proper location in the PC layer, and subsequently died in the autistic cases that showed a reduction in PCs.

The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups.

Autism is a behaviorally defined disorder with deficits in social interaction, communication, atypical behaviors, and restricted areas of interest. Postmortem studies of the brain in autism have shown a broad spectrum of abnormalities in the cerebellum and neocortex, involving limbic regions such as anterior cingulate cortex (ACC, Brodmann's area 24). Using stereological techniques, we analyzed quantitatively cytoarchitectonic subdomains of the ACC (areas 24a, b, c) with regard to cell packing density and cell size. Microscopic examination of the ACC was also done to identify any neuropathologies. Results showed a significant decrease in cell size in layers I-III and layers V-VI of area 24b and in cell packing density in layers V-VI of area 24c. Direct comparisons revealed irregular lamination in three of nine autism brains and increased density of neurons in the subcortical white matter in the remaining cases. Because previous studies have suggested that von Economo neurons (VENs) may be altered in autism, a preliminary study of their density and size was undertaken. VEN density did not differ between autism and control brains overall. However, among the nine autism cases, there were two subsets; three brains with significantly increased VEN density and the remaining six cases with reduced VEN density compared to controls. Collectively, the findings of this pilot study may reflect the known heterogeneity in individuals with autism and variations in clinical symptomotology. Further neuroanatomic analyses of the ACC, from carefully documented subjects with autism, could substantially expand our understanding of ACC functions and its role in autism.

Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction.

It has been widely reported that in autism, the number of Purkinje cells (PCs) is decreased, and recently, decreased expression of glutamic acid decarboxylase 67 (GAD67) mRNA in Purkinje cells also has been observed. However, the autism literature has not addressed key GABAergic inputs into Purkinje cells. Inhibitory basket and stellate cell interneurons in the molecular layer of the cerebellar cortex provide direct key GABAergic input into Purkinje cells and could potently influence the output of Purkinje cells to deep cerebellar nuclei. We investigated the capacity for interneuronal synthesis of gamma-amino butyric acid (GABA) in both types of interneurons that innervate the remaining PCs in the posterolateral cerebellar hemisphere in autism. The level of GAD67 mRNA, one of the isoforms of the key synthesizing enzymes for GABA, was quantified at the single-cell level using in situ hybridization in brains of autistic and aged-matched controls. The National Institutes of Health imaging system showed that expression of GAD67 mRNA in basket cells was significantly up-regulated, by 28%, in eight autistic brains compared with that in eight control brains (mean +/- SEM pixels per cell, 1.03 +/- 0.05 versus 0.69 +/- 0.05, respectively; P < 0.0001 by independent t test). Stellate cells showed a trend toward a small increase in GAD67 mRNA levels, but this did not reach significance. The results suggest that basket cells likely provide increased GABAergic feed-forward inhibition to PCs in autism, directly affecting PC output to target neurons in the dentate nucleus and potentially disrupting its modulatory role in key motor and/or cognitive behaviors in autistic individuals.

Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k.

Although a decreased number of cerebellar Purkinje cells (PCs) in the autistic brain has been widely reported with a variety of qualitative and quantitative methods, the more accurate method of cell counting with modern stereology has not yet been employed. An additional possible problem with prior reports is the use of Nissl staining to identify the PCs, as this can miss cells due to staining irregularities. In the present study, PCs were immunostained for calbindin-D28k (CB), as this has been shown to be a more reliable marker for PCs than the Nissl stain, with more than 99% of the PCs immunopositive (Whitney, Kemper, Rosene, Bauman, Blatt, J Neurosci Methods 168:42-47, 2008). Using stereology and CB immunostaining, the density of PCs was determined in serial sections from a consistently defined area of the cerebellar hemisphere in four control and six autistic brains, with the density of PCs then correlated with the clinical severity of autism. Overall, there was no significant difference in the density of PCs between the autistic and control groups. However, three of six autistic brains had PC numbers that fell within the control range, whereas the remaining three autistic brains revealed a reduction compared with the control brains. These data demonstrate that a reduction in cerebellar PCs was not a consistent feature of these autistic brains and that it occurred without discernible correlation between their density and the clinical features or severity of autism.

Calbindin-D28k is a more reliable marker of human Purkinje cells than standard Nissl stains: a stereological experiment.

In a study of human Purkinje cell (PC) number, a striking mismatch between the number of PCs observed with the Nissl stain and the number of PCs immunopositive for calbindin-D28k (CB) was identified in 2 of the 10 brains examined. In the remaining eight brains this mismatch was not observed. Further, in these eight brains, analysis of CB immunostained sections counterstained with the Nissl stain revealed that more than 99% Nissl stained PCs were also immunopositive for CB. In contrast, in the two discordant brains, only 10-20% of CB immunopositive PCs were also identified with the Nissl stain. Although this finding was unexpected, a historical survey of the literature revealed that Spielmeyer [Spielmeyer W. Histopathologie des nervensystems. Julius Springer: Berlin; 1922. p. 56-79] described human cases with PCs that lacked the expected Nissl staining intensity, an important historical finding and critical issue when studying postmortem human brains. The reason for this failure in Nissl staining is not entirely clear, but it may result from premortem circumstances since it is not accounted for by postmortem delay or processing variables. Regardless of the exact cause, these observations suggest that Nissl staining may not be a reliable marker for PCs and that CB is an excellent alternative marker.

[3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: a multiple concentration autoradiographic study.

Increasing evidence indicates that the GABAergic system in cerebellar and limbic structures is affected in autism. We extended our previous study that found reduced [(3)H]flunitrazepam-labeled benzodiazepine sites in the autistic hippocampus to determine whether this reduction was due to a decrease in binding site number (B (max)) or altered affinity (K (d)) to bind to the ligand. Quantitation of hippocampal lamina demonstrated a 20% reduction in B (max) indicating a trend toward a decreased number of benzodiazepine binding sites in the autistic group but normal K (d) values. A reduction in the number of hippocampal benzodiazepine binding sites suggests alterations in the modulation of GABA(A) receptors in the presence of GABA in the autistic brain, possibly resulting in altered inhibitory functioning of hippocampal circuitry.

Decreased parvalbumin mRNA levels in cerebellar Purkinje cells in autism.

Recent neuropathology studies in human brains indicate that several areas of the prefrontal cortex have decreased numbers of parvalbumin interneurons or decreased parvalbumin expression in Autism Spectrum disorders (ASD) [Hashemi, Ariza, Rogers, Noctor, & Martinez-Cerdeno, 2017; Zikopoulos & Barbas, ]. These data suggest that a deficit in parvalbumin may be a key neuropathology of ASD and contribute to altered GABAergic inhibition. However, it is unclear if a deficit in parvalbumin is a phenomenon that occurs in regions other than the cerebral cortex. The cerebellum is a major region where neuropathology was first detected in ASD over three decades ago [Bauman & Kemper, ]. In view of the documented association between parvalbumin-expressing neurons and autism, the objective of the present study was to determine if parvalbumin gene expression is also altered in Purkinje neurons of the cerebellum. Radioisotopic in situ hybridization histochemistry was used on human tissue sections from control and ASD brains in order to detect and measure parvalbumin mRNA levels at the single cell level in Purkinje cells of Crus II of the lateral cerebellar hemispheres. Results indicate that parvalbumin mRNA levels are significantly lower in Purkinje cells in ASD compared to control brains. This decrease was not influenced by post-mortem interval or age at death. This result indicates that decreased parvalbumin expression is a more widespread feature of ASD. We discuss how this decrease may be implicated in altered cerebellar output to the cerebral cortex and in key ASD symptoms. Autism Res 2017, 10: 1787-1796. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The cerebellum of the brain controls movement and cognition, including memory and language. This study investigated mechanisms of cerebellar function in Autism. Our hypothesis is that parvalbumin, a molecule that controls and coordinate many cellular brain functions, contributes to the excitatory/inhibitory imbalance in Autism. We report that parvalbumin expression is depressed in Purkinje cells of the cerebellum in autism. This finding contributes to elucidate the cellular and molecular underpinings of autism and should provide a direction for future therapies.

Basal ganglia and autism - a translational perspective.

The basal ganglia are a collection of nuclei below the cortical surface that are involved in both motor and non-motor functions, including higher order cognition, social interactions, speech, and repetitive behaviors. Motor development milestones that are delayed in autism such as gross motor, fine motor and walking can aid in early diagnosis of autism. Neuropathology and neuroimaging findings in autism cases revealed volumetric changes and altered cell density in select basal ganglia nuclei. Interestingly, in autism, both the basal ganglia and the cerebellum are impacted both in their motor and non-motor domains and recently, found to be connected via the pons through a short disynaptic pathway. In typically developing individuals, the basal ganglia plays an important role in: eye movement, movement coordination, sensory modulation and processing, eye-hand coordination, action chaining, and inhibition control. Genetic models have proved to be useful toward understanding cellular and molecular changes at the synaptic level in the basal ganglia that may in part contribute to these autism-related behaviors. In autism, basal ganglia functions in motor skill acquisition and development are altered, thus disrupting the normal flow of feedback to the cortex. Taken together, there is an abundance of emerging evidence that the basal ganglia likely plays critical roles in maintaining an inhibitory balance between cortical and subcortical structures, critical for normal motor actions and cognitive functions. In autism, this inhibitory balance is disturbed thus impacting key pathways that affect normal cortical network activity. Autism Res 2017, 10: 1751-1775. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain.